US6245911B1ExpiredUtility
Donepezil polycrystals and process for producing the same
Est. expiryDec 5, 2017(expired)· nominal 20-yr term from priority
C07D 211/32
91
PatentIndex Score
82
Cited by
6
References
21
Claims
Abstract
The present invention provides novel polymorphic crystals (A) to (C) having excellent handling properties and an extremely low content of residual solvent of donepezil used as a precursor for production of donepezil hydrochloride having an excellent action as a medicament, and an industrial process for producing the same. Further, the novel polymorphic crystals (A) to (C) according to the present invention are characterized by the powder X-ray diffraction pattern and/or IR absorption peaks of donepezil represented by the following formula:
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1. A polymorphic crystal (A) of donepezil represented by the following formula:
characterized by having peaks at the following diffraction angles (2 θ ) in its powder X-ray diffraction pattern;
Diffraction angle (2θ, °)
Intensity (I/I O )
7.68
8
8.52
4
8.80
7
10.20
8
10.64
8
11.60
5
12.86
16
14.80
12
15.34
30
15.82
8
16.34
10
16.96
22
17.66
100
19.26
24
20.08
29
20.46
17
20.82
35
21.46
17
21.76
17
22.14
21
22.60
21
23.38
20
24.28
14
24.66
19
25.78
16
and/or peaks at the following wavelengths in its infrared absorption spectrum in potassium bromide: 561.3, 699.8, 743.1, 803.1, 841.3, 858.4, 893.8, 972.5, 1035.7, 1074.7, 1122.9, 1191.8, 1220.3, 1262.4, 1311.8, 1365.6, 1420.5, 1456.6, 1501.3, 1589.0, 1690.1, 2799.6, 2919.1 cm −1 .
2. A polymorphic crystal (B) of donepezil, characterized by having peaks at the following diffraction angles (2 θ ) in its powder X-ray diffraction pattern;
Diffraction angle (2θ, °)
Intensity (I/I O )
5.82
79
11.28
8
11.46
26
11.58
60
11.86
5
12.04
10
12.30
36
13.02
17
13.30
38
13.66
7
13.88
11
14.40
6
15.34
8
15.46
10
16.46
9
16.60
14
16.74
13
18.00
11
18.30
8
18.56
9
19.34
12
19.48
26
19.70
42
20.24
9
20.76
15
21.34
14
21.58
24
21.72
33
21.90
100
22.76
13
22.90
16
23.22
26
23.48
35
23.82
14
24.04
17
24.22
38
24.52
8
24.66
12
25.60
20
28.04
7
and/or peaks at the following wavelengths in its infrared absorption spectrum in potassium bromide: 561.7, 697.5, 738.0, 770.0, 809.6, 861.9, 976.0, 1037.8, 1073.8, 1119.7, 1221.4, 1266.3, 1308.4, 1365.0, 1420.4, 1453.9, 1468.9, 1500.0, 1591.7, 1685.7, 2761.3, 2922.2, 3029.5, 3067.7 cm −1 .
3. A polymorphic crystal (C) of donepezil, characterized by having peaks at the following diffraction angles (20θ) in its powder X-ray diffraction pattern;
Diffraction angle (2θ, °)
Intensity (I/I O )
7.42
3
7.56
4
9.60
4
9.74
10
9.82
15
9.94
23
11.46
4
11.58
6
11.68
9
13.78
8
13.90
17
14.08
29
14.78
14
14.94
25
17.00
100
17.18
48
18.12
10
18.22
10
18.44
8
18.60
12
18.84
19
18.98
17
19.12
17
19.76
17
20.30
9
20.86
13
21.00
18
21.14
25
21.50
48
23.44
26
23.92
17
24.20
10
26.22
13
26.54
25
27.74
7
28.80
7
and/or peaks at the following wavelengths in its infrared absorption spectrum in potassium bromide: 559.8, 648.4, 698.7, 733.5, 746.2, 768.1, 787.2, 818.8, 863.7, 974.0, 1036.4, 1073.0, 1122.1, 1221.3, 1263.0, 1310.3, 1342.3, 1367.5, 1438.1, 1459.1, 1498.6, 1591.9, 1688.1, 2909.3 cm −1 .
4. A process for producing polymorphic crystal (A) of donepezil, which comprises the step of crystallizing a solution of donepezil/methanol-denatured ethanol at 10° C. or less within 20 hours.
5. A process for producing polymorphic crystal (B) of donepezil, which comprises the step of concentrating a solution of donepezil/THF.
6. A process for producing polymorphic crystal (B) of donepezil, which comprises the step of crystallizing a solution of donepezil/methanol-denatured ethanol at 10° C. or less for 20 hours or more.
7. A process for producing polymorphic crystal (C) of donepezil, which comprises the steps of cooling a solution of donepezil/methanol-denatured ethanol at 10° C. or less, and after crystal precipitation, heating it at 20° C. or more after the precipitation of the crystals and further cooling it at 10° C. or less to crystallize.
8. A process for producing polymorphic crystal (C) of donepezil, which comprises the steps of cooling a solution of donepezil/methanol-denatured ethanol, and crystallizing it at 15 to 25° C. after the precipitation of the crystals.
9. A process for producing polymorphic crystal (C) of donepezil, which comprises the step of gradually cooling donepezil/methanol-denatured ethanol.
10. A process for producing polymorphic crystal (A) of donepezil, which comprises the steps of adding seed crystals of polymorphic crystal (A) to a solution of donepezil and crystallizing it at 20° C. or less within 1 hour.
11. A process for producing polymorphic crystal (B) of donepezil, which comprises the steps of adding seed crystals of polymorphic crystal (B) to a solution of donepezil, cooling it at 15° C. or less and then crystallizing it at 20 to 30° C. within 2 hours.
12. A process for producing polymorphic crystal (B) of donepezil, which comprises the steps of adding seed crystals of polymorphic crystal (B) to a solution of donepezil and crystallizing it at 15° C. or less within 1 hour.
13. A process for producing polymorphic crystal (C) of donepezil, which comprises the steps of adding seed crystals of polymorphic crystal (C) to a solution of donepezil, cooling it at 15° C. or less and then crystallizing it at 25 to 35° C. for 2 hours or more and further at 15° C. or less.
14. A process for producing polymorphic crystal (C) of donepezil, which comprises the step of suspending donepezil and seed crystals of polymorphic crystal (C) in a solvent at 20 to 40° C.
15. The process for producing polymorphic crystal (C) of donepezil as claimed in claim 14 , wherein the solvent is a lower alcohol.
16. The process for producing polymorphic crystal (C) of donepezil as claimed in claim 15 , wherein the lower alcohol is at least one selected from the group consisting of methanol, ethanol, n-propanol and i-propanol.
17. The process for producing polymorphic crystal (C) of donepezil as claimed in claim 14 , wherein the solvent is methanol-denatured ethanol.
18. A process for producing polymorphic crystal (A) of donepezil, which comprises the steps of dissolving donepezil in methanol-denatured ethanol, and then adding type-A seed crystals to crystallize.
19. A process for producing polymorphic crystal (B) of donepezil, which comprises the steps of dissolving donepezil in methanol-denatured ethanol, and then adding type-B seed crystals to crystallize.
20. A process for producing polymorphic crystal (C) of donepezil, which comprises the steps of dissolving donepezil in methanol-denatured ethanol, and then adding type-C seed crystals to crystallize.
21. A process for producing polymorphic crystal (C) of donepezil, which comprises the steps of dissolving donepezil in at least one solvent selected from the group consisting of methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, toluene-denatured ethanol, 2-ethoxyethanol, THF, 1,4-dioxane, 1,3-dioxolane, 1,2-dimethoxyethane, methyl acetate, ethyl acetate, isopropyl acetate, acetonitrile, ethyl benzene, cyclohexane, diethyl ether, diisopropyl ether, a mixed solvent of methanol/water, a mixed solvent of acetonitrile/water and a mixed solvent of acetone/hexane, and then adding type-C seed crystals to crystallize.Cited by (0)
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